Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis.

This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group (p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis.

In vivo prostate cancer research: Key interspecies prostate anatomical features for translation medicine.

Prostate cancer (PCa) is a prevalent malignancy affecting men worldwide. Animal models play a crucial role in studying PCa pathology and discovering novel approaches to prevent, detect and treat this disease. However, the challenge of translational medicine is the limited reproducibility and inadequate recapitulation of human conditions in animal models. Therefore, a comprehensive understanding of the macroscopic and microscopic anatomy of the prostate gland among distinct animal species is essential for better translating research findings to clinical practice. This review aims to compare and describe the macroscopic and microscopic anatomy of the prostate gland in humans, rats, and dogs, emphasizing the relevant features. Despite the anatomical differences between these species, rats are a valuable model to study human prostate diseases, once they share some features implicated in carcinogenesis in humans. Dogs, on the other hand, are considered the best model for studying PCa due to the development of spontaneous cancer with a higher incidence when compared with other animals and the development of bone metastases. Moreover, the lymphatic system and the sentinel lymph node role and mapping are similar in dogs and humans. However, it is important to recognize that no animal model can directly mimic all aspects of PCa as the human prostate is anatomically different from that of rats and dogs. Therefore, it is essential to analyze and understand the intra- and interspecies variability when translating research findings into clinical practice. This review highlights the importance of a thorough understanding of the anatomical differences between the prostate gland in humans, rats, and dogs when selecting the appropriate animal model for studying PCa.

Evolution of Models of Prostate Cancer: Their Contribution to Current Therapies.

Prostate cancer (PCa) is among the most frequent cancers worldwide. Nowadays, several therapeutic strategies are available for PCa treatment, namely chemotherapy, immunotherapy, radiotherapy, and hormonal therapy. Despite existing therapeutic approaches, in vitro and in vivo models are essential to better understand cancer development and search for more effective therapies, with a positive impact in cancer patient survival and quality of life. Among several models available, the rat model is the one most frequently used, since it shares anatomical, physiological, pathological, and behavioral features with humans. Animal models can be classified as: spontaneous, chemically-induced; hormonally-induced; implantation of cancer cell lines obtained from humans or from the same species, in the place of disease development or in a different place; and genetically-modified models. The chemically-induced models are among the most frequently used for PCa research. This manuscript provides a comprehensive overview of PCa models, presenting their application, advantages, and disadvantages, and their importance for the development of current therapies for prostate cancer.

Appraising Animal Models of Prostate Cancer for Translational Research: Future Directions.

The growing incidence of prostate cancer has prompted a great investment in basic biology and translational studies to develop new therapies. Multiple animal models have been established to study etiological factors, cancer-preventive strategies and the molecular determinants of aggressiveness and metastases. The rat model of prostate cancer induced by chemical carcinogen N-methyl-N-nitrosourea (MNU) and testosterone exposure has become an important tool to study prostatic carcinogenesis and chemopreventive approaches. Over prolonged treatment, this model develops prostatic lesions that closely mimic those observed in human patients. By modifying the experimental conditions, different research groups have been able to induce a vast spectrum of lesions, ranging from early prostatic intraepithelial neoplasia to metastatic cancer. These carefully tuned experimental settings allowed researchers to test lifestyle interventions, and different pharmacological and chemopreventive strategies. However, this model's great flexibility requires careful planning to ensure that the experimental conditions are adequate to obtain the spectrum of lesions intended. The present review addresses such issues, highlighting the value of the rat prostate cancer model and the multiple challenges and opportunities it offers to researchers worldwide.

Validation of the Rat Model of Prostate Cancer: Correlating Seminal Vesicle Lesions With Dorsolateral Prostate Lesions.

BACKGROUND/AIM: Lesions in the seminal vesicle are described in the most used protocols for prostate cancer (PCa) induction. This study aimed to characterize the lesions of seminal vesicles associated with a protocol of PCa induction in rats to contribute to better characterization of this model. MATERIALS AND METHODS: Forty-five male Wistar Unilever rats were randomly divided into two control groups: CONT1 (n=10) and CONT2 (n=10); and two PCa-induced groups: IND1 (n=10) and IND2 (n=15), sacrificed at 35 and 61 weeks, respectively. Animals from the induced groups were exposed to a multistep protocol for PCa induction. Animals, seminal vesicles and dorsolateral prostate were weighed. Seminal vesicles and dorsolateral prostate were submitted to histopathological and immunohistochemical analysis. RESULTS: Animals in which PCa was induced had a lower mean body weight when compared with the control animals (p<0.05). The relative mean seminal vesicle weight was higher in groups with PCa when compared with control groups (p<0.05). Although the differences were not statistically significant, animals from the IND2 group developed more lesions than animals from the IND1 and CONT2 groups. It is worth noting that the animals from group IND2 developed papillary adenomas and carcinomas in situ, which were not observed in any other group. Similar to observations in seminal vesicles, animals from group IND2 developed more dorsolateral prostate lesions than animals from the IND1 group (p<0.05). CONCLUSION: We observed that the longer the exposure to testosterone was, the greater was the incidence of preneoplastic and neoplastic lesions in both the seminal vesicle and the prostate, suggesting that testosterone exposure affects the spectrum of developed lesions.

An Integrative Approach to Characterize the Early Phases of Dimethylhydrazine-Induced Colorectal Carcinogenesis in the Rat.

This study aimed to characterize an animal model of colorectal cancer (CRC) in the early stages of disease development. Twenty-nine male Wistar rats were divided into two control groups (CTRL1 and CTRL2), receiving EDTA-saline injections and two induced groups (CRC1 and CRC2), receiving 1,2-dimethylhydrazine (DMH) injections for seven consecutive weeks. CRC1 and CTRL1 were euthanized at the 11th week, while CRC2 and CTRL2 were euthanized at the 17th week. DMH treatment decreased microhematocrit values and IL-6, ghrelin, and myostatin serum levels. Histopathological analysis of intestinal sections showed that DMH-treated rats were characterized by moderate to severe epithelial dysplasia. An adenoma was observed in one animal (CRC2 group), and the presence of inflammatory infiltrate at the intestinal level was primarily observed in DMH-treated animals. DMH also induced Ki-67 immunoexpression. The gut microbiota analysis showed a higher abundance of Firmicutes, Clostridia, Clostridiales, Peptostreptococcaceae, Blautia, Romboutsia, and Clostridium sensu stricto in CRC than CTRL rats, whereas Prevotellaceae, Prevotella, Akkermansia, and Lactobacillus levels were more prevalent in CTRL animals. Our results suggest that this model could be helpful to investigate chemoprevention in the early stages of CRC.

An overview of the latest in state-of-the-art murine models for prostate cancer.

INTRODUCTION: Prostate cancer (PCa) is a complex, heterogenous and multifocal disease, which is debilitating for patients and often fatal - due to bone metastasis and castration-resistant cancer. The use of murine models that mimic human disease has been crucial in the development of innovative therapies and for better understanding the mechanisms associated with initiation and progression of PCa. AREAS COVERED: This review presents a critical analysis of murine models for the study of PCa, highlighting their strengths, weaknesses and applications. EXPERT OPINION: In animal models, disease may not occur exactly as it does in humans, and sometimes the levels of efficacy that certain treatments obtain in animal models cannot be translated into clinical practice. To choose the most appropriate animal model for each research work, it is crucial to understand the anatomical and physiological differences between the mouse and the human prostate, while it is also important to identify biological similarities and differences between murine and human prostate tumors. Although significant progress has already been made, thanks to many years of research and study, the number of new challenges and obstacles to overcome mean there is a long and difficult road still to travel.

Toxicological and anti-tumor effects of a linden extract (Tilia platyphyllos Scop.) in a HPV16-transgenic mouse model.

Tilia platyphyllos Scop. is a popular broad-leaved tree, native to Central and Southern Europe. Hydroethanolic extracts rich in phenolic compounds obtained from T. platyphyllos Scop. have shown in vitro antioxidant, anti-inflammatory and antitumor properties. The aim of this work was to evaluate the therapeutic properties of a hydroethanolic extract obtained from T. platyphyllos in HPV16-transgenic mice. The animals were divided into eight groups according to their sex and phenotype. Four groups of female: HPV+ exposed to linden (HPV linden; n = 6), HPV+ (HPV water; n = 4), HPV- exposed to linden (WT linden; n = 5) and HPV- (WT water; n = 4) and four groups of male: HPV+ exposed to linden (HPV linden; n = 5), HPV+ (HPV water; n = 5), HPV- exposed to linden (WT linden; n = 5) and HPV- (WT water; n = 7). The linden (Tilia platyphyllos Scop.) extract was orally administered at a dose of 4.5 mg/10 mL per animal (dissolved in water) and changed daily for 33 days. The hydroethanolic extract of T. platyphyllos consisted of protocatechuic acid and (-)-epicatechin as the most abundant phenolic acid and flavonoid, respectively, and was found to be stable during the studied period. In two male groups a significant positive weight gain was observed but without association with the linden extract. Histological, biochemical, and oxidative stress analyses for the evaluation of kidney and liver damage support the hypothesis that the linden extract is safe and well-tolerated under the present experimental conditions. Skin histopathology does not demonstrate the chemopreventive effect of the linden extract against HPV16-induced lesions. The linden extract has revealed a favourable toxicological profile; however, additional studies are required to determine the chemopreventive potential of the linden extract.

Animal Models of Colorectal Cancer: From Spontaneous to Genetically Engineered Models and Their Applications.

Colorectal cancer is one of the most common gastrointestinal malignancies in humans, affecting approximately 1.8 million people worldwide. This disease has a major social impact and high treatment costs. Animal models allow us to understand and follow the colon cancer progression; thus, in vivo studies are essential to improve and discover new ways of prevention and treatment. Dietary natural products have been under investigation for better and natural prevention, envisioning to show their potential. This manuscript intends to provide the readers a review of rodent colorectal cancer models available in the literature, highlighting their advantages and disadvantages, as well as their potential in the evaluation of several drugs and natural compounds' effects on colorectal cancer.

An Overview of Current Alternative Models for Use in the Context of Prostate Cancer Research.

Prostate cancer is one of the most commonly diagnosed cancers worldwide, particularly in elderly populations. To mitigate the expected increase in prostate cancer-related morbidity and mortality as a result of an expanding aged population, safer and more effective therapeutics are required. To this end, plenty of research is focusing on the mechanisms underlying cancer initiation and development, the metastatic process and on the discovery of new therapies. While animal models are used (mainly rats and mice) for the study of prostate cancer, alternative models and methods are increasingly being considered to replace, or at least reduce, the number of animals used in this particular field of research. In this review, we cover some of the alternative models that are currently available for use in the study of prostate cancer, including: mathematical models; 2-D and 3-D cell cultures; microfluidic devices; the chicken egg chorioallantoic membrane-based model; and zebrafish embryo-based models. The main advantages and limitations, as well as some examples of applications, are given for each type of model. According to our analysis, immortalised cell lines are still the most commonly used models in the field of prostate cancer research. However, the use of alternative models for prostate cancer research will likely become more prevalent in the coming years partly because of the increasing societal pressure to reduce the numbers of laboratory animals. In this context, the development and dissemination of effective non-animal alternative models assumes particular relevance and will be instrumental in leveraging their success. Taking these perspectives into account, we believe that technological advances will lead to more effective cell culture systems, namely 3-D cultures or organ-on-a-chip devices, which can be used to replace animal-based models in prostate cancer research.

Dietary Supplementation with Chestnut (Castanea sativa) Reduces Abdominal Adiposity in FVB/n Mice: A Preliminary Study.

The production of chestnut (Castanea sativa Miller) is mostly concentrated in Europe. Chestnut is recognized by its high content of antioxidants and phytosterols. This work aimed to evaluate the effects of dietary chestnut consumption over physiological variables of FVB/n mice. Eighteen FVB/n male 7-month-old mice were randomly divided into three experimental groups (n = 6): 1 (control group) fed a standard diet; 2 fed a diet supplemented with 0.55% (w/w) chestnut; and 3 supplemented with 1.1% (w/w) chestnut. Body weight, water, and food intake were recorded weekly. Following 35 days of supplementation, the mice were sacrificed for the collection of biological samples. Chestnut supplementation at 1.1% reduced abdominal adipose tissue. Lower serum cholesterol was also observed in animals supplemented with chestnut. There were no significant differences concerning the incidence of histological lesions nor in biochemical markers of hepatic damage and oxidative stress. These results suggest that chestnut supplementation may contribute to regulate adipose tissue deposition.

Modelling human prostate cancer: Rat models.

Prostate cancer is the second most common cancer in men, affecting approximately 1.1 million men worldwide. In this way, the study of prostate cancer biopathology and the study of new potential therapies is of paramount importance. Several rat models were developed over the years to study prostate cancer, namely spontaneous models, chemically-induced models, implantation of cancer cell lines and genetically-engineered models. This manuscript aimed to provide the readers with an overview of the rat models of prostate cancer, highlighting their advantages and disadvantages, as well as, their applications.

Implementation of Humane Endpoints in a Urinary Bladder Carcinogenesis Study in Rats.

BACKGROUND/AIM: This study aimed to evaluate the utility of several biological parameters for the prediction of tumor development and animal welfare in a rat model of urinary bladder cancer. MATERIALS AND METHODS: The control group (n=9) received tap water while the test group (n=12) received the carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water. A score sheet with biological variables was used to monitor animals' welfare. Body weight, food and drink consumption and rectal temperature were measured weekly. Blood and urine samples were collected. RESULTS: Animals from the control group exhibited a slightly higher body weight and body weight gain. The final urine volume was higher in BBN group (p<0.05). All animals from the BBN group exhibited macroscopic hematuria at 35th week. Four animals were anemic in the last week of the experiment. CONCLUSION: The routine control of hematuria was a useful non-invasive biomarker of disease progression that may be used as a potential earlier humane endpoint. Animals did not show clinical signs of suffering that justified their sacrifice before the end of the study.